Báo cáo y học: "Improvement in symptoms and signs in the forefoot of patients with rheumatoid arthritis treated with anti-TNF therapy" ppsx

This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0, which permits unrestricted use, distrib

AND ANKLE RESEARCH

Open Access

R E S E A R C H

© 2010 Bowen et al; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in

Research

Improvement in symptoms and signs in the

forefoot of patients with rheumatoid arthritis

treated with anti-TNF therapy

Catherine J Bowen*†1,7, Christopher J Edwards4,2,6,5, Lindsey Hooper†1,5, Keith Dewbury†3, Madeleine Sampson†3, Sally Sawyer†4, Jane Burridge†1 and Nigel K Arden†4,6,7

Abstract

Background: Inhibition of tumour necrosis factor (TNF) is an effective way of reducing synovitis and preventing joint

damage in rheumatoid arthritis (RA), yet very little is known about its specific effect on foot pain and disability The aim

of this study was to evaluate whether anti-TNF therapy alters the presence of forefoot pathology and/or reduces foot pain and disability

Methods: Consecutive RA patients starting anti-TNF therapy (infliximab, etanercept, adalimumab) were assessed for

presence of synovial hypertrophy and synovitis in the 2nd and 5th metatarso-phalangeal (MTP) joints and plantar forefoot bursal hypertrophy before and 12 weeks after therapy Tender MTP joints and swollen bursae were established clinically by an experienced podiatrist and ultrasound (US) images were acquired and interpreted by a radiologist Assessment of patient reported disease impact on the foot was performed using the Manchester Foot Pain and Disability Index (MFPDI)

Results: 31 patients (24 female, 7 male) with RA (12 seronegative, 19 seropositive) completed the study: mean age 59.6

(SD 10.1) years, disease duration 11.1 (SD 10.5) years, and previous number of Disease Modifying Anti Rheumatic Drugs 3.0 (1.6) Significant differences after therapy were found for Erythrocyte Sedimentation Rate (t = 4.014, p < 0.001), C-reactive protein (t = 3.889, p = 0.001), 28 joint Disease Activity Score (t = 3.712, p = 0.0001), Visual Analog Scale (t = 2.735, p = 0.011) and Manchester Foot Pain and Disability Index (t = 3.712, p = 0.001)

Presence of MTP joint synovial hypertrophy on US was noted in 67.5% of joints at baseline and 54.8% of joints at twelve weeks Presence of plantar forefoot bursal hypertrophy on US was noted in 83.3% of feet at baseline and 75% at twelve weeks Although there was a trend for reduction in observed presence of person specific forefoot pathology, when the frequencies were analysed (McNemar) this was not significant

Conclusions: Significant improvements were seen in patient reported foot pain and disability 12 weeks after

commencing TNF inhibition in RA, but this may not be enough time to detect changes in forefoot pathology

Background

Tumour Necrosis Factor (TNF) inhibition is known to be

an effective way of reducing synovial hypertrophy and

preventing erosions in patients who have rheumatoid

arthritis (RA) [1,2] Unfortunately studies to date have

tended to focus on the hand joints and little is known of

the effect of TNF inhibition on the foot

Prevalence rates for pain and swelling in the feet in RA are high [3] and this correlates with patient reported out-come measures of impairment, activity limitation and participation restriction [4] In fact, most patients with

RA continue to report frequent and disabling foot pain despite pharmacological management, including TNF inhibition [5-8]

We have previously reported higher prevalence rates of forefoot pathology detectable by ultrasound (US) than by clinical examination [9] Clinical assessment techniques are relatively insensitive in assessment of RA disease

* Correspondence: cjb5@soton.ac.uk

1 School of Health Sciences, University of Southampton, Southampton, UK

† Contributed equally

Full list of author information is available at the end of the article

within the foot, and clinically under reported

manifesta-tions of RA within the foot appear to be a common

find-ing in imagfind-ing studies [10-12] Although investigators

have reported the demographic of TNF inhibition, none

have formally assessed the effects on foot symptoms and

pathology

US is beneficial in monitoring the progression of active

inflammation in rheumatoid arthritis [13] and in the

monitoring of biologic therapy [14-16] The aim of this

study was to evaluate by means of US, the effects of

anti-TNF therapy in RA patients with specific focus on the

forefoot using the hypothesis that forefoot symptoms,

like those of hand joint symptoms, would improve with

this intervention

Methods

A prospective study design was utilized, in which the

forefeet of a consecutive cohort of patients with RA

diag-nosed according to the ACR criteria (modified 1987) [17]

starting anti-TNF therapy (infliximab, etanercept or

adal-imumab) was examined clinically and by US at baseline

and twelve weeks following therapy

Participant selection

Participants were recruited from patients with RA

attending the Rheumatology

Department, Southampton University Hospitals NHS

Trust who were starting anti-TNF therapy In compliance

with the declaration of Helsinki, Local Research Ethics

Committee approval and informed consent was secured

prior to data collection

We enrolled consecutive patients with RA who were

about to start anti-TNF therapy and were considered

appropriate for this study Our recruitment criteria

excluded any patients from the study if they had a history

of previous forefoot surgery, received a corticosteroid

injection to the forefoot within the 3 months prior to this

study, had an additional musculoskeletal disease (e.g

pri-mary osteoarthritis, gout, Paget's disease, systemic lupus

erythematosus), or had a serious medical (other than RA)

or psychological disorder that would prevent completion

of the study protocol

Data collection

Data collection took place between February 2005 and

June 2007 The longer time allowed for sufficient

num-bers to be recruited as only a limited number of patients

were starting anti-TNF therapy during that period All

clinical assessments took place within the Wellcome

Trust Clinical Research Facility, Southampton General

Hospital All US scans were undertaken by a Radiologist

(KD or MS) and took place in the Department of

Radiol-ogy, Southampton General Hospital On each visit, the

same treatment bays and US facilities were utilised An

experienced podiatrist assessed both forefeet of all partic-ipants (CJB) and the presence of any swelling and/or ten-derness was recorded To reduce recall bias, all investigators (CJE, SB, CJB, KD and MS) were blinded to each other's results and all were blinded to their own baseline assessment of the individual patient being assessed

Assessment of demographic and clinical characteristics

Prior to data collection, the diagnosis of RA was con-firmed by the supervising consultant (CJE) Following acceptance into the study all participants were assessed

by a trained specialist rheumatology nurse (SB) and Dis-ease Activity Scores (DAS-28) were calculated [18] General demographic and clinical data of age, gender, disease duration, presence of rheumatoid factor, current medication, and current and previous use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) were obtained from the Rheumatology Department database and clinical notes

Clinical characteristics included visual analog scale (VAS 100 mm) assessment for the patient's global impres-sion of health, and assessment of disease activity by the number of painful, tender and swollen joints calculated as Disease Activity Scores (DAS-28)

Foot assessments

Foot symptoms were determined by the use of a validated patient administered index, the Manchester Foot Pain and Disability Index (MFPDI) [19] The MFPDI asked participants to rate a series of 19 questions and took approximately five minutes for participants to complete The forefeet of all participants were assessed by an expe-rienced podiatrist (CJB) for MTP joint synovitis and plantar forefoot bursitis All foot assessments were con-ducted at the same time as the US scans

Other clinical data

Laboratory assessments included blood tests for C-reac-tive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) on the same day as the foot assessments and US scans

Imaging data

US examinations were performed using a Philips HDI

5000 System (Royal Philips Electronics, Netherlands) in B-Mode using a 5-10 MHz linear probe Images were recorded in two perpendicular planes, longitudinal and transverse and performed moving from proximal to distal

as suggested by the EULAR (European League against Rheumatism) working group for musculoskeletal US in rheumatology guidelines [20] A dorsal approach to detect MTP joint synovial hypertrophy, synovitis and erosion with the patient in a supine position was also

adopted as recommend by the EULAR guidelines, [21]

(see Figure 1a)

Observations of MTP joint synovial hypertrophy,

syno-vitis and erosions by US (grey scale and power Doppler

where possible) were conducted within just two joints in

each foot (second and fifth MTP joints) from both a

plan-tar and dorsal approach Synovial hypertrophy, synovitis

and erosions were registered as being present or absent

We have previously reported on the selection of the

sec-ond and fifth MTP joints as being representative of the

forefoot joints [22] and this has also been corroborated by

others more recently [23] On US synovial hypertrophy

appears as hypoechoic intra-articular tissue [24] and if

this is inflammatory active synovitis, it shows as a

posi-tive power Doppler US signal which gives a colour

spec-tral map superimposed onto the grey scale image [25]

Any synovial hypertrophy, synovitis and erosion within

the second and fifth MTP joints identified by US were

recorded on a data sheet

At the time of this study there was no standard

defini-tion for imaging of clinically apparent plantar forefoot

bursal swelling by US We therefore decided to use a

plantar approach as we were interested in determining

the prevalence of bursal hypertrophy within the plantar

forefoot region Two types of bursal hypertrophy may

occur within the plantar forefoot region, intermetatarsal

or sub-metatarsal Intermetatarsal bursal hypertrophy

appears on US as a well defined fluid collection with

hypoechoic or anechoic zones usually bulging more than

1 mm under the metatarsal head level [10,26]

Sub-meta-tarsal bursal hypertrophy is attributed to adventitial

bur-sitis and defined on US as anechoic or heterogenous collections of fluid within the sub-metatarsal fat pad [26] For each plantar scan the transducer was placed trans-versely and moved laterally from the first MTP joint with its centre at the level of the metatarsal heads (see Figure 1b) The process was repeated longitudinally (see Figure 1c) The presence of bursal hypertrophy across the plan-tar forefoot region identified by US was recorded on a data sheet

Statistical analyses

Data evaluation and statistical analysis were performed using SPSS version 17.0 software (SPSS, Chicago IL) The data was initially examined using histograms and scatter plots to identify 'outliers' that may have occurred due to data entry bias or normal biological outliers The preva-lence of MTP joint synovial hypertrophy, synovitis, ero-sions and plantar bursal hypertrophy per foot and per anatomical site within the forefoot is described via the mean, standard deviations and frequencies Paired t-tests for parametric continuous data were performed to deter-mine whether there were differences in patient reported foot pain and disability (MFPDI) between baseline and twelve weeks as well as the clinical variables, ESR, CRP, global well- being (VAS) and DAS-28 To determine change in the presence of forefoot pathology, the pres-ence of MTP joints with synovial hypertrophy, MTP joints with synovitis, and total numbers of plantar fore-foot bursal hypertrophy per fore-foot were tested for differ-ences using a McNemar test for categorical data of related groups

Figure 1 Photographs demonstrating the dorsal longitudinal approach to assess the MTP joints (a), and the plantar transverse (b) and lon-gitudinal (c) positions of the US transducer to assess the plantar forefoot area.

A B C

Participant demographics and clinical characteristics

From thirty two patients with RA, starting anti-TNF

ther-apy recruited, one patient was excluded at the baseline

visit due to having the wrong diagnosis and one was

excluded from the US foot scans due to having open

wounds on the plantar forefoot area Four participants

did not return for the ultrasound scans at the twelve week

visit (see Figure 2) We did not exclude anyone at the

ini-tial participant recruitment session; however a small

number of individuals did decline to take part in the

study Thirty one patients therefore started the study, 24

female and 7 male patients, 12 rheumatoid-factor

nega-tive and 19 rheumatoid-factor posinega-tive The majority of

participants had established RA with a mean age of 59.58

(SD 10.14; range 37-76) years, and duration of RA 11.1

(SD 10.52; range 1-39) years In line with NICE guidance

[27], all had previously been taking DMARDs, (mean 3.0,

SD 1.6, per person) A comparison of demographic and

clinical characteristics at baseline and twelve weeks can

be seen in Table 1

There was a statistically significant reduction in patient

reported foot pain and disability after twelve weeks of

anti-TNF therapy (t = 3.712, p = 0.001) Similarly all other

clinical disease measures were significantly reduced: ESR

(t = 4.014, p < 0.001), CRP (t = 3.889, p = 0.001), DAS-28

(t = 3.712, p = 0.001) and global wellbeing VAS (t =

2.7351, p = 0.011)

Prevalence of forefoot pathology in patients with RA

detected by US

At both baseline and twelve weeks a higher prevalence of

forefoot pathology per individual was detected by US

than by clinical examination (see Table 2) There was an

observed trend for reduction in presence of person

spe-cific US detectable plantar forefoot bursal hypertrophy

and MTP joint synovial hypertrophy between baseline

and twelve weeks (see Figure 3)

Observed presence of MTP joint synovial hypertrophy

by US from 60 feet (120 joints) indicates presence in

67.5% (81/120 joints) at baseline and 54.8% (57/104

joints) at twelve weeks At twelve weeks 25.9% (27/104

joints) had changed from MTP joint synovial hypertro-phy being present to absent, and 13.5% (14/104 joints) changed from MTP joint synovial hypertrophy being absent to present

For presence of synovitis detectable by US Doppler, from 44 feet (N = 16 data missing) 10.2% (9/88 joints) was noted at baseline and 6.9% (5/72 joints from 36 feet was noted at twelve weeks Of these, 11.1% (8/72 joints) had changed from MTP joint synovitis being present to absent and small number, 5.6% (4/72 joints) had changed from MTP joint synovitis being absent to present at twelve weeks

Frequency of observed presence of US detectable plan-tar forefoot bursal hypertrophy was higher than that noted in MTP joint synovial hypertrophy but changes fol-lowed a similar pattern US detectable forefoot bursal hypertrophy was noted in 83.3% (50/60) of feet at base-line and 75% (39/52) of feet at twelve weeks At twelve weeks 19.2% (10/52) of feet had changed from US detect-able forefoot bursal hypertrophy being present to absent and 9.6% (5/52) changed from US detectable forefoot bursal hypertrophy being absent to present

When the frequencies for joint specific and foot spe-cific presence of US and clinically detectable MTP joints with synovial hypertrophy, MTP joints with synovitis, and plantar forefoot bursal hypertrophy per individual were analysed no significant differences were found between the baseline data and twelve weeks (Table 2)

Discussion

To our knowledge, our results are the first to show that patient reported foot pain and disability reduces signifi-cantly following TNF inhibition Furthermore, using US, our results indicate that there is a trend towards reduc-tion in US detectable MTP joint synovial hypertrophy, synovitis and plantar forefoot bursal hypertrophy follow-ing twelve weeks of TNF inhibition

The trend towards improvement was also noted in the clinical and laboratory assessments of RA disease status (ESR, CRP and DAS-28) These reductions were statisti-cally significant demonstrating that TNF inhibition was

Table 1: Demographic and clinical characteristics of the study participants at baseline and twelve weeks by mean (standard deviation)

*Overall well being

Figure 2 Participant recruitment flow chart of returnees and non returnees at baseline and twelve weeks.

Consecutive patients with RA who were about to start anti-TNF therapy were recruited between February 2005–June 2007

31 participants recruited

into the study

12 replied with definite no, did not want to take part

1 responded yes but then was excluded during the baseline assessment due to having psoriatic arthritis

2 withdrew after baseline assessments due to being too ill to attend

1 excluded due to open foot

wounds

2 withdrew after baseline assessments due to personal reasons

31 participants

completed all

demographic and clinical

assessments

30 participants

completed all US scans

22 participants

completed all Doppler

US scans

26 participants

completed all US scans

18 participants

completed all Doppler

US scans

N=8 missing data for Doppler scans

26 returnees at 12 weeks

32 responders

effective in controlling the disease process in the RA

par-ticipants within this study, consistent with previous

reports [1,2]

Pragmatically, whilst patient reported foot symptoms

did significantly reduce, it may be hypothesized that

treatment switches off the disease process of RA, but

twelve weeks was not enough time for sonographic

evi-dence of MTP joint synovitis, synovial hypertrophy and

plantar bursal hypertrophy to regress within the forefeet

In previous work, within the MCP joints of the hands a

reduction in sonographically detectable synovial

hyper-trophy was noted at eighteen weeks following infliximab

therapy, and this was reported as a significant reduction

at 110 weeks [2] In explaining US detection of synovitis

within joints, Brown et al [28] report that synovium may

become chronically thickened and less reversible in

established disease This was typically demonstrated

within our sample in which the majority of participants

had established RA with a mean duration of 11.1 years

Using Doppler US 11.1% of MTP joints examined that

showed a positive US Doppler response at baseline had

none after twelve weeks, yet synovial hypertrophy

remained evident on US in 54.8% of MTP joints at twelve

weeks This is consistent with a recent study where 42

joints (bilateral glenohumeral, elbows, wrists, MCPs,

proximal interphalangeal, knees, tibiotalar, midtarsal and MTPs) were assessed with the most common joints with

US detectable synovitis being the wrist, hands and feet and power Doppler US signal occurring less frequently in the MTP joints [29]

Foot symptoms were not inclusion criteria within our study, yet the high prevalence detectable by US was sur-prising There are suggestions that clinically evident dis-ease improves more quickly following effective treatment than disease assessed by modern imaging techniques [11] In a previous study of patients treated with anti-TNF therapy, 90% demonstrated clinical remission at week 14, but none had absence of imaging synovitis [29] We can infer this from our findings too, whereby a much higher prevalence of US detectable plantar MTP joint synovial hypertrophy and plantar forefoot bursal hypertrophy was evident than that detectable by clinical examination at both baseline and twelve weeks

Of further note, in a minority of participants, clinical disease activity and well being scores improved but the prevalence of US detectable MTP joint synovial hypertro-phy and plantar forefoot bursal hypertrohypertro-phy increased This anomalous finding could be attributable to imper-fect reproducibility of the US measurements, a reported phenomenon in the use of US [30], although as

technol-Table 2: Comparison of the prevalence of MTP joint and foot specific US detectable and clinically detectable pathology of the study participants at baseline and twelve weeks by frequency (N)

Key: R = Right; L = Left; 2 = second MTP joint; 5 = fifth MTP joint

ogy has improved reliability in US techniques have

improved [31] Alternatively, although the MFPDI

improves with treatment, the questionnaire is developed

for foot complaints in general and does not focus on the

forefoot [19] Therefore it is possible that the difference

between self-reported symptoms in US detectable signs

in the forefoot may also be attributable to a faster

recov-ery of other foot joints than the MTP joints Increased

mechanical stresses, possibly as mobility improved for

those patients, rather than an increase in episodes of

syn-ovial hypertrophy and bursal hypertrophy due to the

dis-ease process of RA may also be the cause of prolonged US

detectable synovial hypertrophy within the forefeet

Mechanical and gait data would have been useful to

explore this concept further van der Leeden, Steultjens et

al [32] demonstrated correlations of radiographic MTP

joint deformity with peak pressure and pressure time

integrals for the first and fourth MTP joints and

correla-tions of high forefoot pressures with pain in RA

partici-pants In a later systematic review of foot related

measures, van der Leeden, Steultjens et al [33]

recom-mend considering both self report and performance based instruments when investigating foot problems associated with RA We chose to focus on clinical assess-ment of foot pathology, foot disability and foot pain and

no account was taken of the mechanical forces of foot function during gait as this was not feasible within the confines of our study Others, having investigated the association between foot disabilities, mechanics of func-tion and foot mechanics, recommend that future predic-tion models may be enhanced by combining imaging based identification of foot pathology with mechanical data [4]

No techniques have yet been developed to detect differ-ences between mechanically related inflamed hypertro-phied synovium and active inflammatory synovium related to disease activity in RA within the foot Brown, Conaghan et al [28] highlight that grey scale US primarily detects hypertrophy of the synovium but does not differ-entiate between inflammatory and non inflammatory synovitis For future studies the further use of power Doppler US, Gadolinium enhanced MRI and/or biopsy

Figure 3 A simple bar chart representing the percentages of cases of US detectable forefoot bursal hypertrophy and MTP joint synovial hypertrophy at baseline and following twelve weeks of anti-TNF therapy.

bursal hypertrophy

baseline

12 weeks

83.3

75

67.5

54.8 100

50

0

for histological analysis of forefoot pathology would be

needed to achieve this as well as the development of a

technique that includes the effect of foot mechanics

This study has several strengths and a number of

potential limitations Strengths include that it was a

prag-matic clinical study representative of secondary care in

the UK In addition, a sample of patients with RA at the

same stage of treatment was investigated Furthermore,

patient reported clinical outcomes including disease

activity and foot specific measures were used

Potential limitations include the fact the presence of US

detectable MTP joint synovitis, synovial hypertrophy and

bursal hypertrophy within the forefoot was not validated

by any other 'gold standard' imaging technique, such as

Magnetic Resonance Imaging (MRI) or by histological

analysis through biopsy Soft tissue swelling at the level of

the MTP joints in the plantar forefoot area can be related

to other pathology such as tenosynovitis or rheumatoid

nodules that could be better differentiated using MRI

[34,35] Due to its restricted availability MRI was not

fea-sible for our study Others have attempted to validate

imaging findings using fresh cadavers [36] however this

technique was also not a feasible option during our

clini-cal study

Limitations relating to the sample and time frame also

have to be highlighted The sample was relatively small;

therefore generalizibility to the whole population of

patients with RA needs to be confirmed The time frame

of twelve weeks gave only two points of assessment over a

relatively short period Although providing useful

infor-mation, more time points over a longer time period

would have allowed variations in individual foot states to

be monitored more effectively

Conclusions

We have demonstrated that patient reported foot pain

and disability does reduce significantly following twelve

weeks of TNF inhibition We have also provided some

evidence that suggests forefoot pathology in RA may

improve following a short period of TNF inhibition;

how-ever further evidence over a longer time period is

required to confirm that this is sustained The findings

further indicate that the use of US imaging of the foot

would be more beneficial than clinical examination alone

in the refinement of diagnosis and the implementation of

effective care pathways for patients who have foot

symp-toms and are starting TNF inhibition

List of abbreviations

TNF: Tumour necrosis factor; RA: Rheumatoid arthritis;

MTP: Metatarso-phalangeal; US: Ultrasound; MFPDI:

Manchester foot pain and disability index; SD: Standard

deviation; DMARDs: Disease modifying anti-rheumatic

drugs; ESR: Erythrocyte sedimentation rate; CRP:

C-reactive protein; DAS-28: Disease activity score of 28

swollen and tender joints; VAS: Visual analog scale; ACR: American College of Rheumatology; EULAR: European League Against Rheumatism; NICE: The National Insti-tute for Health and Clinical Excellence; MRI: Magnetic resonance imaging

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

CB conceived of the study, carried out the ultrasound foot study of patients with RA treated with anti-TNF therapy, participated in the clinical assessment

of foot status and drafted the manuscript CE participated in the design of the study, carried out the assessment of eligibility of RA patients for anti-TNF ther-apy and helped to draft the manuscript LH participated in the data analysis and helped to draft the manuscript KD and MS participated in the design of the study and performed the US assessments SS participated in the study design and coordination JB participated in the design of the study and helped

to draft the manuscript NA participated in the conception and design of the study and helped to draft the manuscript All authors read and approved the final manuscript.

Author Details

1 School of Health Sciences, University of Southampton, Southampton, UK,

2 Research Development and Support Unit, University of Southampton, Southampton, UK, 3 Ultrasound Department, Department of Radiology, Southampton University Hospitals NHS Trust, Southampton General Hospital, Southampton, UK, 4 Department of Rheumatology, Southampton University Hospitals NHS Trust, Southampton General Hospital, Southampton, UK,

5 Wellcome Trust Clinical Research Facility, Southampton University Hospitals Trust, Southampton General Hospital, Southampton, UK, 6 MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK and 7 NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK

References

1 Hau M, Kneitz C, Tony HP, Keberle M, Jahns R, Jenett M: High resolution ultrasound detects a decrease in pannus vascularisation of small finger joints in patients with rheumatoid arthritis receiving treatment with

soluble tumour necrosis factor alpha receptor (etanercept) Ann

Rheum Dis 2002, 61:55-58.

2 Taylor PC, Steuer A, Gruber J, McClinton C, Cosgrove DO, Blomley MJ, Marsters PA, Wagner CL, Maini RN: Ultrasonographic and radiographic results from a two-year controlled trial of immediate or one-year-delayed addition of infliximab to ongoing methotrexate therapy in

patients with erosive early rheumatoid arthritis Arthritis Rheum 2006,

54:47-53.

3 van der Leeden M, Steultjens MP, Ursum J, Dahmen R, Roorda LD, Schaardenburg DV, Dekker J: Prevalence and course of forefoot impairments and walking disability in the first eight years of

rheumatoid arthritis Arthritis Rheum 2008, 59:1596-1602.

4 Turner DE, Helliwell PS, Siegel KL, Woodburn J: Biomechanics of the foot

in rheumatoid arthritis: identifying abnormal function and the factors

associated with localised disease 'impact' Clin Biomech (Bristol, Avon)

2008, 23:93-100.

5 Rojas-Villarraga A, Bayona J, Zuluaga N, Mejia S, Hincapie ME, Anaya JM: The impact of rheumatoid foot on disability in Colombian patients

with rheumatoid arthritis BMC Musculoskelet Disord 2009, 10:67.

6 Rome K, Gow PJ, Dalbeth N, Chapman JM: Clinical audit of foot problems

in patients with rheumatoid arthritis treated at Counties Manukau

District Health Board, Auckland, New Zealand J Foot Ankle Res 2009,

2:16.

7 Otter SJ, Lucas K, Springett K, Moore A, Davies K, Cheek L, Young A, Walker-Bone K: Foot pain in rheumatoid arthritis prevalence, risk factors and

management: an epidemiological study Clin Rheumatol 29:255-271.

8 Grondal L, Tengstrand B, Nordmark B, Wretenberg P, Stark A: The foot: still the most important reason for walking incapacity in rheumatoid

arthritis: distribution of symptomatic joints in 1,000 RA patients Acta

Orthop 2008, 79:257-261.

Received: 1 March 2010 Accepted: 17 June 2010 Published: 17 June 2010

This article is available from: http://www.jfootankleres.com/content/3/1/10

© 2010 Bowen et al; licensee BioMed Central Ltd

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Foot and Ankle Research 2010, 3:10

9 Bowen CJ, Culliford D, Dewbury K, Sampson M, Burridge J, Hooper L,

Edwards CJ, Arden NK: The clinical importance of ultrasound detectable

forefoot bursae in rheumatoid arthritis Rheumatology (Oxford) 2010 in

press.

10 Koski JM: Ultrasound detection of plantar bursitis of the forefoot in

patients with early rheumatoid arthritis J Rheumatol 1998, 25:229-230.

11 Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E,

Wakefield RJ, O'Connor PJ, Emery P: Presence of significant synovitis in

rheumatoid arthritis patients with disease-modifying antirheumatic

drug-induced clinical remission: evidence from an imaging study may

explain structural progression Arthritis Rheum 2006, 54:3761-3773.

12 Wakefield RJ, Freeston JE, O'Connor P, Reay N, Budgen A, Hensor EM,

Helliwell PS, Emery P, Woodburn J: The optimal assessment of the

rheumatoid arthritis hindfoot: a comparative study of clinical

examination, ultrasound and high field MRI Ann Rheum Dis 2008 in

press.

13 McNally EG: Ultrasound of the small joints of the hands and feet:

current status Skeletal Radiol 2008, 37:99-113.

14 Iagnocco A, Perella C, Naredo E, Meenagh G, Ceccarelli F, Tripodo E, Basili

S, Valesini G: Etanercept in the treatment of rheumatoid arthritis:

clinical follow-up over one year by ultrasonography Clin Rheumatol

2008, 27:491-496.

15 Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Karim Z, Quinn M,

Wakefield R, Hensor E, Conaghan PG, Emery P: Disease remission state in

patients treated with the combination of tumor necrosis factor

blockade and methotrexate or with disease-modifying antirheumatic

drugs: A clinical and imaging comparative study Arthritis Rheum 2009,

60:1915-1922.

16 Haavardsholm EA, Ostergaard M, Hammer HB, Boyesen P, Boonen A, van

der Heijde D, Kvien TK: Monitoring anti-TNFalpha treatment in

rheumatoid arthritis: responsiveness of magnetic resonance imaging

and ultrasonography of the dominant wrist joint compared with

conventional measures of disease activity and structural damage Ann

Rheum Dis 2009, 68:1572-1579.

17 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS,

Healey LA, Kaplan SR, Liang MH, Luthra HS, et al.: The American

Rheumatism Association 1987 revised criteria for the classification of

rheumatoid arthritis Arthritis Rheum 1988, 31:315-324.

18 Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB,

van Riel PL: Modified disease activity scores that include

twenty-eight-joint counts Development and validation in a prospective longitudinal

study of patients with rheumatoid arthritis Arthritis Rheum 1995,

38:44-48.

19 Garrow AP, Papageorgiou AC, Silman AJ, Thomas E, Jayson MI, Macfarlane

GJ: Development and validation of a questionnaire to assess disabling

foot pain Pain 2000, 85:107-113.

20 Backhaus M, Burmester GR, Gerber T, Grassi W, Machold KP, Swen WA,

Wakefield RJ, Manger B: Guidelines for musculoskeletal ultrasound in

rheumatology Ann Rheum Dis 2001, 60:641-649.

21 Scheel AK, Schmidt WA, Hermann KG, Bruyn GA, D'Agostino MA, Grassi W,

Iagnocco A, Koski JM, Machold KP, Naredo E, et al.: Interobserver

reliability of rheumatologists performing musculoskeletal

ultrasonography: results from a EULAR "Train the trainers" course Ann

Rheum Dis 2005, 64:1043-1049.

22 Bowen CJ, Dewbury K, Sampson M, Sawyer S, Burridge J, Edwards CJ,

Arden NK: Musculoskeletal ultrasound imaging of the plantar forefoot

in patients with rheumatoid arthritis: inter-observer agreement

between a podiatrist and a radiologist J Foot Ankle Res 2008, 1:5.

23 Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W,

Sattler H, Albrecht K, Kaufmann J, Becker K, et al.: Evaluation of a novel

7-joint ultrasound score in daily rheumatologic practice: a pilot project

Arthritis Rheum 2009, 61:1194-1201.

24 O'Connor PJ, Grainger AJ: Ultrasound imaging of joint disease Imaging

2002, 14:188-201.

25 Balint PV, Mandl P, Kane D: "All that glistens is not gold" separating

artefacts from true Doppler signals in rheumatological ultrasound

Ann Rheum Dis 2008, 67:141-142.

26 Gregg JM, Schneider T, Marks P: MR imaging and ultrasound of

metatarsalgia the lesser metatarsals Radiol Clin North Am 2008,

46:1061-1078 vi-vii

27 NICE: Clinical Guidelines for Adalimumab, etanercept and infliximab for

the treatment of rheumatoid arthritis In National Institute for Clinical

Excellence London; 2007

28 Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor

E, Wakefield RJ, O'Connor PJ, Emery P: An explanation for the apparent dissociation between clinical remission and continued structural

deterioration in rheumatoid arthritis Arthritis Rheum 2008,

58:2958-2967.

29 Wakefield RJ, Freeston JE, Hensor EM, Bryer D, Quinn MA, Emery P: Delay

in imaging versus clinical response: a rationale for prolonged treatment with anti-tumor necrosis factor medication in early

rheumatoid arthritis Arthritis Rheum 2007, 57:1564-1567.

30 Joshua F, Lassere M, Bruyn GA, Szkudlarek M, Naredo E, Schmidt WA, Balint

P, Filippucci E, Backhaus M, Iagnocco A, et al.: Summary findings of a

systematic review of the ultrasound assessment of synovitis J

Rheumatol 2007, 34:839-847.

31 Cheung P, Ruyssen-Witrand A, Gossec L, Paternotte S, Le Bourlout C, Mazieres M, Dougados M: Reliability of clinical self-evaluation of swollen and tender joints in rheumatoid arthritis: A comparison study

with ultrasonography, physician and nurse assessments Arthritis Care

Res 2010 in press.

32 van der Leeden M, Steultjens M, Dekker JH, Prins AP, Dekker J: Forefoot joint damage, pain and disability in rheumatoid arthritis patients with

foot complaints: the role of plantar pressure and gait characteristics

Rheumatology (Oxford) 2006, 45:465-469.

33 van der Leeden M, Steultjens MP, Terwee CB, Rosenbaum D, Turner D, Woodburn J, Dekker J: A systematic review of instruments measuring foot function, foot pain, and foot-related disability in patients with

rheumatoid arthritis Arthritis Rheum 2008, 59:1257-1269.

34 Ashman CJ, Klecker RJ, Yu JS: Forefoot pain involving the metatarsal

region: differential diagnosis with MR imaging Radiographics 2001,

21:1425-1440.

35 Studler U, Mengiardi B, Bode B, Schottle PB, Pfirrmann CW, Hodler J, Zanetti M: Fibrosis and adventitious bursae in plantar fat pad of forefoot: MR imaging findings in asymptomatic volunteers and MR

imaging-histologic comparison Radiology 2008, 246:863-870.

36 Theumann NH, Pfirrmann CW, Chung CB, Mohana-Borges AV, Haghighi P, Trudell DJ, Resnick D: Intermetatarsal spaces: analysis with MR

bursography, anatomic correlation, and histopathology in cadavers

Radiology 2001, 221:478-484.

doi: 10.1186/1757-1146-3-10

Cite this article as: Bowen et al., Improvement in symptoms and signs in the

forefoot of patients with rheumatoid arthritis treated with anti-TNF therapy

Journal of Foot and Ankle Research 2010, 3:10